We have screened 108 non-small cell lung tumors for mutational alterations in the p53 gene (exons 5 through 8) using polymerase chain reaction and denaturing gel electrophoresis techniques. Thirty-four cases (32%) had aberrant band migrations. The following DNA-sequencing step confirmed the mutations in all these samples. Seventy-six % of the mutations were found at G:C base pairs. Of all the mutations found, 29% were GC to AT, 29% GC to TA, 15% AT to GC, 12% GC to CG, and 3% AT to CG. The other mutations (12%) were deletions or insertions of one base pair. The frequency of p53 mutations among heavy smokers was higher than in nonsmokers (P = 0.047; odds ratio, 6.75; 95% confidence interval, 0.80-57). We examined p53 mutations in relation to genotypes of GSTmu1 and H-ras1. Our data showed that nearly all heavy smokers with transversion mutations were homozygous for the GSTmu1 null allele (10 of 11). The frequency of such mutations was significantly higher for patients with two null alleles (10 of 25) than for those with at least one allele intact (1 of 18) (P = 0.011; odds ratio, 11.33; 95% confidence interval, 1.29-99.3). This study indicated that rare alleles at the variable number of tandem repeats region flanking the H-ras protooncogene are negatively associated to the presence of p53 mutations in the tumors (P = 0.009).